We wish to establish an integrated laboratory research program employing rodent models to study cellular mechanisms mediating the maintenance of enduring neurological deficits commonly produced by Traumatic Brain Injury (TBI). The central hypothesis is that TBI produces changes in specific proteins and/or neurotransmitter systems which contribute to the maintenance of enduring neurological deficits following injury. Prevention and/or reversal of these changes will improve neurological status after TBI. The proposal includes three laboratory projects. Project 1 examines the hypothesis that severe TBI in rats produces long term disturbances in central cholinergic neurotransmission which contribute to memory (and motor) deficits. Using biochemical, biological and immunohistochemical techniques to monitor aspects of cholinergic neurotransmission following TBI, this project will correlate cholinergic deficiencies with behaviorally-assessed memory disability. Project 2 examines the hypothesis that TBI induces specific cytoskeletal derangements in neurons that contribute to enduring neuro-behavioral deficits caused by injury. Descriptions of these cytoskeletal derangements will provide information on the cytological topography of injury to neurons following mechanical insults. This proposal will investigate qualitatively and quantitatively changes in cytoskeletal protein content caused by TBI including MAP2, spectrin, tau, and neurofilament proteins. The proposal will also determine whether changes in cytoskeletal protein content are produced by shifting the balance between protein degradation and synthesis. Project 3 will examine the hypothesis that TBI increases the level of amyloid precursor protein and that production of specific pools of APP fragments are associated with TBI pathology. This project will perform regional analyses of total APP mRNA and protein at different time after TBI to determine relationships between changes in APP, cellular localization and light microscopic histopathology. The proposal will also determine if TBI produces differential increases in mRNA and protein for specific isoforms of APP and if activation of specific factors e.g., fos, jun, HSF, possibly by IL-1 and other pathways, will increase amyloid precursor protein expression. Each of the three projects incorporate studies of the effects of therapeutic manipulations. These manipulations will provide information on possibly causal relationships between neurological deficits and cellular pathology after injury and also suggest potential new therapies for the management of traumatically brain injured patients. The project will be supported by the Laboratory Core whose functions include: 1) production of experimental brain injury, 2) standardized behavioral assessments ensure, 3) general histological processing of brain tissue, and 4) compilation of a centralized computer database.